Breast cancer arises in the epithelium of the organ. The epithelium consists of several cell types, each of which has a particular propensity to ‘transform’ into cancer. It is thought that the cell of origin confers upon the resulting tumor a particular phenotype, with the most aggressive tumors being derived from relatively undifferentiated cells whose replicative capacity is large. These include those designated as stem cells, capable of giving rise to the entire epithelium, and progenitor cells, capable of giving rise to progeny whose differentiation is restricted. The hierarchical distribution of these lineages poses that stem cells have the most replicative and regenerative capacity, while progenitors have less and differentiated cells have the least. Thus, the composition of the breast epithelium, in terms of distribution and frequency of specific cell types, can affect the risk of developing cancer and will also affect the type of cancer (Visvader (2011) Nature 469(7330): 314-322).
A case in point is the breast of women who carry germline mutations in BRCA1 and have a substantially greater risk of developing cancer of the breast, as well as the ovary and uterus. Breast cancer is heterogeneous. At least five distinct breast cancers subtypes have been identified based on any one of morphology, marker frequency or gene expression or a combination thereof. While breast cancer is most prevalent in women after the age of 60, BRCA1 mutation carriers have a much greater risk of developing an aggressive type of breast cancer even before the age of 40. This type of cancer is frequently designated triple-negative because it lacks expression of estrogen receptor (ER) and PR, and does not amplify HER2. The absence of markers suggests that it originates from undifferentiated cells. This conjecture is supported by recent studies showing that BRCA1 mutations cause an expansion of progenitor cells in breast (Liu, et al. 2008. Proc Natl Acad Sci USA 105(5): 1680-1685; Proia, et al. 2011. Cell stem cell 8(2): 149-163).
Breast cancer is the most common cancer in women and the second leading cause of cancer-related mortality in women. About 10% of breast cancer cases cluster in families. Mutations in the breast cancer susceptibility (BRCA) genes are correlated with a high percentage of these familial cases. Indeed, BRCA1 mutations account for the most common form of genetically inherited breast cancer. Germline mutations of BRCA1 have been detected in approximately 90% of familial breast and ovarian cancers and approximately 50% of familial breast cancer alone (Hill et al. 1997 Br. J. Surg. 84, 1334-1339; Casey. 1997. Curr. Opin. Oncol. 9, 88-93. Women that inherit germ cell mutations of BRCA1 are at up to 80% risk of developing breast cancer and 50% risk of developing ovarian cancer. BRCA mutation carriers are also typically diagnosed with invasive breast cancer about ten years earlier than patients presenting with sporadic breast cancer. BRCA1 associated cancers, moreover, exhibit distinct histopathology, immunohistochemistry, cytogenetics, and gene expression profiles that differ from those of either non-familial breast cancer cases or BRCA2-related breast cancer.
Even though most BRCA1 mutations lead to estrogen receptor negative breast cancer, treatment with estrogen increases cancer risk in BRCA1 mutation carriers. Also there is a high degree of hyperplastic lesions in women with mutations in the BRCA1 gene when their breast tissue is examined following prophylactic mastectomies performed to avoid development of breast cancer (Hoogerbrugge N J Clin Oncology 2003, 41-45).
Women with certain hyperplastic lesions of the breast are at high risk for breast cancer. There is clinical evidence that treatment with tamoxifen can prevent the development of cancer by about 50%. Tamoxifen treatment is problematic in that it has many side effects and makes women almost completely estrogen deficient as if they were menopausal. Serious side effects include uterine cancer, pulmonary embolism, and strokes. Although well tolerated by some patients, many patients experience one or more unpleasant side effects and some experience life threatening complications as a result of tamoxifen treatment. Indeed, some patients consider the side effects of tamoxifen treatment to be unacceptable.
With respect to BRCA1 mutation carriers, however, even tamoxifen, which is effective in preventing most sporadic breast cancers, is not known to be an effective preventive measure (King M C et al, JAMA 2001 2251-2256). Due to their high risk for developing breast cancer and limited preventive options, many BRCA1 mutation carriers feel compelled to turn to prophylactic bilateral mastectomy as the only proven method for preventing development of breast cancer (Meijers-Heijboer, H N Eng J Med 2001 159-164). Bilateral oophorectomy is also an available option, but is known to be less protective (Rebbeck, T R et al J Natl Cancer Inst 1999, 1475-1479).
Antiestrogens or aromatase inhibitors have also been employed as a means of preventing breast cancer in women with preneoplastic breast lesions such as atypical hyperplasia. While effective in women with atypical hyperplasia, these approaches may cause serious side effects and symptoms of menopause which can be unacceptable, and also a high incidence of osteoporosis. These techniques are also utilized to prevent recurrence of breast cancer in women with ductal carcinoma in situ. Ruan et al. have proposed that inhibition of insulin-like growth factor 1 (IGF-I or IGF-1) activity might be able to substitute for estrogen inhibitors because IGF-I is essential for estrogen and progesterone action in the mammary gland (Ruan W et al (2005) Endocrinology 146(3):1170-1178).
Somatostatin and somatostatin-related peptides are a family of peptides that have broad spectrum biological actions and exert suppressive effects on a large variety of cells, functioning as endogenous growth inhibitors. Naturally-occurring peptides have a short half life because they are rapidly inactivated by endogenous peptidases and therefore efforts have been made to develop more stable peptides. The three most extensively tested analogs are SMS 201-995 (octreotide), BIM 23014 (lanreotide) and RC-160 (vapreotide) (Lamberts S W J et al (1991) Endocrin Rev 12:450-482). Somatostatins bind somatostatin receptor(s), with subtypes SSTR-1 to SSTR-5 identified, cloned, and functionally characterized (Patel Y C et al (1995) Life Sci 57:1249-1265; Patel Y C et al (1996) Metabolism 45 (suppl 1):31-38; Reisine T and Bell G I (1995) Endocrin Rev 16:427-442; Buscail L et al (1995) PNAS USA 92:1580-1584; Bell G I and Reisine T (1993) Trends Neurosci 16:34-38). Octreotide (Sandostatin®) and vapreotide have a low affinity for SSTR-1, a high affinity for SSTR-2, and relatively low affinity for SSTR-3 and SSTR-5.
Somatostatin analogs have an established role in the management of patients with pituitary and neuroendocrine tumors but only a potential role in the treatment of solid tumors, including breast cancer. In this tumor type in particular, somatostatin analogs showed limited activity either when used alone or when given in combination with tamoxifen or bromocriptine. Moreover, none of the randomized trials that compared the therapeutic value of the combination of octreotide and tamoxifen versus tamoxifen alone showed any advantage in favor of combined treatment. Therefore, although the great majority of trials failed to show major side effects attributable to somatostatin analogs, the use of these compounds was limited to controlled trials (Boccardo, F. and Amoroso D. (2001) Chemotherapy 47:62-77).
The somatostatin analog called SOM230 prevents mammary gland development in rats via two mechanisms (Ruan, W et al (2006) Mol Endocrinology 20(2):426-436). One of them is an inhibitory effect on growth hormone secretion from the pituitary which can cause reduction of serum IGF-I. The other is a direct inhibition of IGF-I action in the mammary gland as demonstrated by a reduction in IRS-1 phosphorylation in the mammary gland. It has been postulated that this effect of SOM230 is mediated by either somatostatin receptor subtype (SSTR) 3 or 5 and that this causes an increase in IGF binding protein 5 (IGFBP5) which in turn blocks the local action of IGF-I in the mammary gland (Ruan, W et al (2006) Mol Endocrinology 20(2):426-436).
There is clearly a need for improved modalities and compounds for prevention of progression to breast cancer in at-risk individuals. The compound tamoxifen, which is in use for breast cancer prevention, has significant side effects due to its blocking effect of circulating estrogen. While tamoxifen is administered to antagonize estrogen action at the estrogen receptor (ER) in the breast, its systemic effects trigger signs and symptoms consistent with menopause. An alternative treatment that would provide targeted preventive therapy, without causing symptoms or signs of estrogen deficiency is therefore desired.
The citation of references herein shall not be construed as an admission that such is prior art to the present invention.